rs150813402

Description

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and absent from unaffected control subjects (Easton 2016); This variant is associated with the following publications: (PMID: 26921362)

Variant summary: BRIP1 c.3236T>C (p.Ile1079Thr) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (7.8e-06 vs 6.3e-05), allowing no conclusion about variant significance. The c.3236T>C has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.I1079T variant (also known as c.3236T>C), located in coding exon 19 of the BRIP1 gene, results from a T to C substitution at nucleotide position 3236. The isoleucine at codon 1079 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was reported in 1 of 13,213 patients diagnosed with invasive breast cancer and was not reported in any of the 5,242 healthy control subjects (Easton DF et al. J. Med. Genet., 2016 05;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces isoleucine with threonine at codon 1079 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26921362). This variant has been identified in 2/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1079 of the BRIP1 protein (p.Ile1079Thr). This variant is present in population databases (rs150813402, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 128185). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.